Thesis (Ph. D.)--Ohio State University, 2007. / Full text release at OhioLINK's ETD Center delayed at author's request

Thesis (Ph.D.)--McMaster University, 2005. / Supervisor: John F. Valliant. Includes bibliographical references. Also available online.

Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2004. / Includes bibliographical references (leaves 247-267). Also available in electronic version. Access restricted to campus users.

Indiana University-Purdue University Indianapolis (IUPUI) / A novel route has been developed for the solid-phase synthesis of N-carboxyalkyl unnatural amino acids as potential metalloprotease inhibitors. The key step involves a nitrogen alkylation of resin-bound amino acids with -bromoesters. Alkylation of the benzophenone imine of glycine on Wang resin was used to introduce unnatural amino acid side chains onto the resin-bound glycine. The benzyl -bromoesters [BrCH(R2)CO2Bn], starting materials for the C-N bond construction, were prepared in solution by diazotization of naturally-occurring amino acids to form the -bromoacids, followed by benzylation of the carboxylic acid to form the benzyl -bromoesters. N-Alkylation of the resin-bound, unnatural amino acids with the benzyl -bromoesters and subsequent cleavage from resin gave the benzyl ester monoacid intermediates. Exploration of reverse-phase cyano-silica gel chromatography and preparative liquid chromatography provided effective purification of the benzyl ester intermediates. Hydrolysis of the analytically pure benzyl ester monoacids afforded clean products as the diacids. The two points of variation introduced through the two on-resin alkylation steps, C-alkylation of the benzophenone imine of glycine and N-alkylation with the benzyl -bromoesters, allow for the combinatorial synthesis of a library of target compounds.

Solid-phase syntheses of two 14-membered ring peptidomimetics were done to determine whether or not a beta-turn structure can facilitate macrocyclization. NMR methods, together with CD and QMD calculations, do not fully support this assumption. However, cyclizations of more ordered structures like those of compounds 2 were more efficient than those for highly strained ring systems like 1. A small library of 18-membered ring peptidomimetics that accommodate an extra amino acid residue was synthesized on resin. Their syntheses were not complicated by head-to-tail dimer impurity, unlike those for previously synthesized 14-membered systems. These larger macrocycles exhibit beta-turn structures as verified by NMR, CD and QMD techniques. Moreover, two compounds in this series (3a and 3g) were shown to have agonistic properties for TrkC in cell survival assays. Dimerization of monovalent mimics was achieved first by modifying the organic template so that monovalent mimics with requisite functional groups can be synthesized. Second, the monovalent units were dimerized using sequential nucleophilic substitutions on fluorescently labeled dichlorotriazine. Our rationale to make bivalent compounds out of monovalent ones was justified when compound 4 was shown to bind TrkA with a 20 nM affinity. Reactions of amino acids with NH4SCN under acylating conditions produced 2-thiohydantoins in which the nitrogen of the amino acid (N1) was acylated. This was proven by 2-D NMR which showed no cross-peak between the NH signal observed and the Cα±-H of the amino acid. When the compound was deacylated, a new NH signal appeared and the corresponding cross-peak with the Cα±-H was observed. Solution-phase syntheses of non-peptidic mimics were achieved by doing a double substitution on a dihalogenated nitrobenzene scaffold. Sonogashira and SNAr reactions were done to install the required side-chains to give the desired compounds. These non-peptidic compounds can be easily adapted to our DTAF-Inp dimerization protocol since the nitro groups can be easily reduced. Attempts to make a spirotetracyclic peptidomimetic with three side chain mimics were done by synthesizing the spirocyclic diketopiperazine precursor. The synthesis of the DKP was achieved by making the cyclic quaternary amino acid that was coupled to another amino acid via the HOAt-EDC method. This protocol gave dipeptides in high yields. These dipeptides were deprotected and cyclized to the DKP under mildly acidic conditions in toluene.

Solid-phase syntheses of two 14-membered ring peptidomimetics were done to determine whether or not a beta-turn structure can facilitate macrocyclization. NMR methods, together with CD and QMD calculations, do not fully support this assumption. However, cyclizations of more ordered structures like those of compounds 2 were more efficient than those for highly strained ring systems like 1. A small library of 18-membered ring peptidomimetics that accommodate an extra amino acid residue was synthesized on resin. Their syntheses were not complicated by head-to-tail dimer impurity, unlike those for previously synthesized 14-membered systems. These larger macrocycles exhibit beta-turn structures as verified by NMR, CD and QMD techniques. Moreover, two compounds in this series (3a and 3g) were shown to have agonistic properties for TrkC in cell survival assays. Dimerization of monovalent mimics was achieved first by modifying the organic template so that monovalent mimics with requisite functional groups can be synthesized. Second, the monovalent units were dimerized using sequential nucleophilic substitutions on fluorescently labeled dichlorotriazine. Our rationale to make bivalent compounds out of monovalent ones was justified when compound 4 was shown to bind TrkA with a 20 nM affinity. Reactions of amino acids with NH4SCN under acylating conditions produced 2-thiohydantoins in which the nitrogen of the amino acid (N1) was acylated. This was proven by 2-D NMR which showed no cross-peak between the NH signal observed and the Cα±-H of the amino acid. When the compound was deacylated, a new NH signal appeared and the corresponding cross-peak with the Cα±-H was observed. Solution-phase syntheses of non-peptidic mimics were achieved by doing a double substitution on a dihalogenated nitrobenzene scaffold. Sonogashira and SNAr reactions were done to install the required side-chains to give the desired compounds. These non-peptidic compounds can be easily adapted to our DTAF-Inp dimerization protocol since the nitro groups can be easily reduced. Attempts to make a spirotetracyclic peptidomimetic with three side chain mimics were done by synthesizing the spirocyclic diketopiperazine precursor. The synthesis of the DKP was achieved by making the cyclic quaternary amino acid that was coupled to another amino acid via the HOAt-EDC method. This protocol gave dipeptides in high yields. These dipeptides were deprotected and cyclized to the DKP under mildly acidic conditions in toluene.

Thesis (M.S.)--University of Missouri-Columbia, 2003. / Typescript. Includes bibliographical references (leaves 109-112). Also available on the Internet.

Thesis (M.S.)--University of Missouri-Columbia, 2003. / Typescript. Includes bibliographical references (leaves 109-112). Also available on the Internet.

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第20929号 / 理博第4381号 / 新制||理||1630(附属図書館) / 京都大学大学院理学研究科化学専攻 / (主査)教授 杉山 弘, 教授 三木 邦夫, 教授 秋山 芳展 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DGAM

Described herein are three projects centered on the synthesis of conducting polymer derivatives for various applications. The first is the novel synthesis of 9,9-dioctylfluorene-co-benzothiadiazole [F8BT] oligomers through solid phase synthesis for the study of the thermodynamics and kinetics of electron transfer in the polymer. The second endeavor involves the synthesis of a series of 4”,3’’’-dialkyl-2,2’:5’,2”:5”,2’’’:5’’’,2’’’’:5’’’’,2’’’’’-sexithiophenes for the studies on crystal packing and surface deposition of organic p-type semiconducting materials. Lastly is described the development of a conducting metallopolymer based on the ligand 2,6-Bis(4-(2,2’-bithiophen-5-yl)-1H-pyrazol-1-yl)pyridine for use in a drug delivery system. / text